Virginia was the only child of James Eldridge Cassidy (1898–1957), the town iceman (later a grocer), and Edith (née Grisham) Cassidy (1901–1968), a nurse anesthetist. During her high school years, she worked as a waitress at a local restaurant. Following her graduation from high school, Virginia moved to Shreveport, Louisiana, to study to be a nurse anesthetist like her mother. During her training in Shreveport, she met her first husband, William Jefferson Blythe, Jr., whom she married in a civil ceremony in 1943, just before he shipped out for World War II military duty. Upon completion of her training, she returned to Hope, Arkansas. When her husband was discharged, he picked her up and they moved for four months to Chicago, Illinois.

She moved back to her parents while she and William were in the process of getting a new home in the Hope area. While William was on his way back to Hope, he was killed in an automobile accident, three months before Bill Clinton's birth. In 1950, Virginia married car salesman Roger Clinton, Sr., the father of the second of her two boys, Roger Jr. Clinton was an alcoholic and was physically and mentally abusive to Virginia and her boys. He did not adopt Bill but Bill took his surname legally in 1962 at his own request. He told his mother that it would be easier if they all had the same last name. Roger Sr. and Virginia divorced in 1962, but remarried a few months later.[citation needed]

Following Roger's death from cancer in 1967, Virginia Clinton married hairdresser Jeff Dwire in 1969; he subsequently died of complications of diabetes in 1974. On January 17, 1982, she married Richard Kelley (1915–2007), an executive at a food distribution brokerage firm. Their marriage lasted until her death on January 6, 1994 from complications of breast cancer, at the age of 70, at her home in Hot Springs, Arkansas. She died less than a year after her son became the 42nd President of the United States on January 20, 1993. She is buried alongside her first husband at Rose Hill Cemetery in Hope.